1. Field of the Invention
This invention relates to the use of carbonyl amino benzoates for treatment of auto-immune diseases in humans and animals; and pharmaceutical compositions comprising a carbonyl amino benzoate and at least one pharmaceutical excipient.
2. Related Art
U.S. patent application Ser. No. 748,631, filed Jun. 25, 1985, and assigned to the assignee of this invention, discloses that compounds of the following Formula: ##STR1## wherein: a is an integer of 0-4;
A is a bond, or alkylene having one to eight carbon atoms; PA1 R is hydrogen, phenyl, imidazolyl or cycloalkyl having three to six carbon atoms, wherein the phenyl, imidazolyl or cycloalkyl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R.sup.1).sub.2, --NO.sub.2, halo or lower alkylthio having one to four carbon atoms, and, PA1 each R' is independently selected from the group consisting of lower alkyl having one to six atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, lower alkylthio or halo-lower alkyl having one to four carbon atoms, halo, ##STR2## in which each R.sup.1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having one to four carbon atoms or --CH.sub.2 CH.sub.2 OH, PA1 each R.sup.2 is independently lower alkyl having one to four carbon atoms, PA1 A is an alkylene group if R is hydrogen, and the pharmaceutically acceptable acid addition salts thereof, are useful as serine protease inhibitors in humans and animals. U.S. patent application Ser. No. 748,631 is hereby fully incorporated by reference into this disclosure. PA1 R is alkyl, phenyl, (imidazol-4-yl)methyl or cycloalkyl having three to six carbon atoms, wherein the phenyl or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having one to four carbon atoms, lower alkoxy having one to four carbon atoms, --N(R.sup.1).sub.2, --NO.sub.2, halo, and lower alkylthio having one to four carbon atoms; and each R' is independently selected from the group consisting of hydroxy, lower alkyl having one to six carbon atoms, lower alkenyl having two to six carbon atoms, lower alkoxy having one to six carbon atoms, halo-lower alkyl or lower alkylthio having one to six carbon atoms, halo, ##STR4## in which each R.sup.1 is independently hydrogen or lower alkyl having one to four carbon atoms, or together form a piperidine or piperazine ring optionally substituted at the ring nitrogen with lower alkyl having one to four carbon atoms or --CH.sub.2 CH.sub.2 OH; PA1 each R.sup.2 is independently lower alkyl having one to four carbon atoms. PA1 methyl 6-methyl-2-[4-(N-triphenylmethyl)imidazolyl]methoxycarbonylamino benzoate; PA1 methyl 6-ethyl-2-[4-(N-triphenylmethyl)imidazolyl]methoxycarbonylamino benzoate; PA1 methyl 6-chloro-4-nitro-2-[4-(N-triphenylmethyl)imidazolyl]methoxycarbonylamino benzoate; PA1 methyl 6-ethylthio-4-bromomethyl-2-[4-(N-triphenylmethyl)imidazolyl]methoxycarbon ylamino benzoate; PA1 methyl 4-amino-6-ethyl-2-[4-(N-triphenylmethyl)imidazolyl]methoxycarbonylamino benzoate, and PA1 methyl 4-amino-6-methyl-2-[4-(N-triphenylmethyl)imidazolyl]methoxycarbonylamino benzoate.
Many chronic, inflammatory conditions of man and animals fluctuate in intensity with concomitant fluctuations in pain and swelling. While the acute symptoms of many of the rheumatic diseases, such as rheumatoid arthritis, may be controlled by the administration of analgesic, anti-inflammatory drugs such as aspirin and aspirin-like drugs, the underlying disease process is not affected. Tissue destruction in diseases such as rheumatoid arthritis, encephalomyelitis, multiple sclerosis, type II diabetes and the like, proceeds inexorably in the face of palliative treatment with aspirin-like drugs, and results, eventually, in substantial and debilitating loss of function.
Since many chronic, inflammatory conditions of man and animals are now known to result from an attack by the body's immune system on some portion or tissue of the body (a situation called auto-immunity), attempts have been made to treat such diseases with agents which suppress the function of the immune system. Cortico-steroids, for example, suppress the ability of the body to mount an effective immune response. Corticosteroids are non-selective in this respect and suppress both humoral (antibody) and cell-mediated (delayed type hypersensitivity) responses, although only one or the other response may be involved in a particular auto-immune disease. Corticosteroids find some utility in controlling acute flares of auto-immune diseases, but they are not curative and the potential for side effects precludes their extended use. Similarly, immunosuppressive drugs derived from cancer chemotherapy, such as cyclophosphamide and methotrexate, find certain utility in treatment of auto-immune diseases, and on rare occasions may even produce long term remission.
Nevertheless, these drugs are also non-selective and suppress all aspects of the immune system. During their administration the body is rendered incapable of mounting effective resistant to invading micro-organisms (viruses, bacteria, fungi, yeasts, protozoa), and life-threatening infections are a frequent result. Additionally, prolonged use of the general immuno-suppressive agents results in an increased incidence of various cancers.
Significant therapeutic advances in the treatment of auto-immune diseases requires the discovery and use of agents which are much more selective in their effects on the immune response system: i.e., agents which suppress only those processes involved in a particular disease, leaving the remaining processes unaffected and competent to combat infectious diseases and the like.
At an early stage of discovery, since drugs cannot be tested directly in man, recourse is had to testing or screening in animal models of inflammation and auto-immune disease. Such models include:
1. Carrageenan-induced paw edema in the rat. This is a non-specific model of acute inflammation which does not involve the immune system. A solution of carrageenan injected into the foot pad of a rat causes reddening, swelling and pain which is maximal three to six hours after administration and then resolves. Aspirin-like drugs and corticosteroids administered at the appropriate doses effectively inhibit the inflammatory response caused by the carrageenan injection. Immuno-suppressive agents are not effective under these circumstances.
2. Adjuvant-induced arthritis in the rat. This is an immune-based animal model of rheumatoid arthritis and other rheumatic diseases. A mixture of Freund's Complete Adjuvant (consisting of saline, mineral oil, and the dried, killed micro-organism Mycobacterium butyricum) is injected into the skin of a rat. An initial, local inflammatory response (1 to 4 days) is followed by a generalized inflammatory condition (day 9 onwards) in which the animal mounts an immune response against its own cartilaginous tissues. The disease process is particularly evident in peripheral joints which show reddening, swelling and tenderness. Inflammatory cells invade these joints, and release enzymes and other factors which produce much tissue destruction. As the disease progresses, both joints and underlying bone are destroyed such that loss of mobility results. It is believed that both humoral (anti-body) and cell-mediated immunity may be involved in this model. All manifestations of this disease in rats are effectively controlled by daily administration of appropriate doses of corticosteroids, cyclophosphamide and aspirin-like drugs. Whereas aspirin-like drugs effectively prevent tissue destruction resulting from this induced disease in rats, they are not effective in preventing the tissue destruction associated with the inexorable course of rheumatoid arthritis in man.
3. Experimental allergic encephalomyelitis in the rat. This is an immune-based animal model of demyelinating diseases which shows resemblance to multiple sclerosis. A mixture of syngeneic spinal cord homogenate in Freund's Complete Adjuvant injected subcutaneously into the rat induces an anti-immune response directed against the myelin covering the nerves of the central nervous system. Beginning nine days after the injection, the rat begins to lose body weight and between the twelfth and sixteenth day shows symptoms of paralysis which may be as mild as urinary incontinence and tail flaccidity or as severe as complete body paralysis. These symptoms result from attack of immune cells on the nerves with subsequent destruction and loss of ability to transmit the nervous impulses necessary for controlling muscle function. Daily treatment with cyclophosphamide (starting on the first day) gives protection from the weight loss and paralysis suffered by the animals. This is consistent with the general immuno-suppressive effects of this drug. Corticosteroid treatment also prevents the appearance of paralytic symptoms, but the dose of corticosteroid required is such that the corticosteroid itself causes weight loss greater than that produced by the disease alone. In contrast to their action in Adjuvant-inducted Arthritis in the rat, aspirin-like drugs are completely ineffective in preventing the symptoms and weight loss of experimental allergic encephalomyelitis.